Abstract
Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=−0.09±0.01 mmol l−1, P=3.4 × 10−12), T2D risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early insulin secretion (β=−0.07±0.035 pmolinsulin mmolglucose−1, P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l−1, P=4.3 × 10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l−1, P=1.3 × 10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
Highlights
Fasting glucose and insulin are intermediate traits for type 2 diabetes
We identified a novel association of a nonsynonymous single nucleotide variants (SNVs) (A316T, rs10305492, MAF 1⁄4 1.4%) in the gene encoding the receptor for glucagon-like peptide 1 (GLP1R), with the minor (A) allele associated with lower fasting glucose (FG) (b 1⁄4 À 0.09±0.01 mmol l À 1, P 1⁄4 3.4 Â 10 À 12, variance explained 1⁄4 0.03%, Table 1 and Fig. 1), but not with fasting insulin (FI) (P 1⁄4 0.67, Supplementary Table 1)
Given the role of incretin hormones in post-prandial glucose regulation, we further investigated the association of A316T with measures of postchallenge glycaemia, including 2-h glucose, and 30 min-insulin and glucose responses expressed as the insulinogenic index[19] in up to 37,080 individuals from 10 studies (Supplementary Table 2)
Summary
Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility. Genome-wide association studies (GWAS) highlight the role of common genetic variation in quantitative glycaemic traits and susceptibility to type 2 diabetes (T2D)[1,2]. Recent efforts have identified the role of low frequency and rare coding variation in complex disease and related traits[7,8,9,10], and highlight the need for large sample sizes to robustly identify such associations[11]. Our approach identifies novel coding and non-coding variants and extends the allelic and functional spectrum of genetic variation underlying diabetes-related quantitative traits and T2D susceptibility
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